2,4,6-trisubstituted-s-triazines

ABSTRACT

THIS DISCLOSURE DESCRIBES COMPOUNDS OF THE CLASS OF N2-(POLYCYCLOALKYL) - N4,N6-BIS(ALIPHATIC OR ALICYCLIC MELAMINES USEFUL AS ANTI-MYCOBACTERIAL AGENTS.

United States Patent 3,577,417 2,4,G-TRISUBSTITUTED-s-TRIAZINES Margot Louise Cantrall, New City, Martin Leon Sassiver,

Monsey, and Robert Gordon Shepherd, South Nyack, N.Y., assignors to American Cyanamid Company, Stamford, Conn. No Drawing. Filed May 22, 1969, Ser. No. 827,048 Int. Cl. C07d 55/22 US. Cl. 260249.6 10 Claims ABSTRACT OF THE DISCLOSURE This disclosure describes compounds of the class of N (polycycloalkyl) N ,N -bis(aliphatic or alicyclic) melamines useful as anti-mycobacterial agents.

BRIEF SUMMARY OF THE INVENTION This invention relates to new derivatives of melamine and, more particularly, is concerned with novel compounds which may be represented by the following general formula:

NEE-R wherein R is adamantyl or bicyclo[2.2.l]heptyl and R and R are each selected from the group consisting of normal alkyl of from 1 to 8 carbon atoms, secondary alkyl of from 4 to 8 carbon atoms, tertiary alkyl of from 4 to 11 carbon atoms, lower cycloalkyl, methyl-substituted lower cycloalkyl, adamantyl, bicyclo[2.2.l]heptyl and methyl-substituted bicyclo[2.2.l]hetpyl.

DETAILED DESCRIPTION OF THE INVENTION Suitable secondary alkyl groups of from 4 to 8 carbon atoms contemplated by the present invention are, for example,

3-methyl-2-butyl,

3 ,3-dimethyl-2-butyl, S-methyl-Z-pentyl, 4-methyl-2-pentyl, 3-ethyl-2-pentyl, 3,3-dimethyl-2-pentyl, 3 ,4-dimethyl-2-pentyl, 4,4-dimethyl-2-pentyl,

5-methyl-3-hexyl, 4-ethyl-3-hexyl, 4,4-dimethyl-3 -hexyl, 5,5 -dimethyl-3-hexyl, 6-methyl-2-hepty1, 6-methyl-3-heptyl, 6-methyl-4-heptyl, etc.

Suitable tertiary alkyl groups of from 4 to 11 carbon atoms contemplated by the present invention are, for example,

tert-butyl,

tert-pentyl, 2-methyl-2-pentyl, 2-methyl-2-hexyl, 2-methyl-2-heptyl, 2,3-dimethyl-2-butyl, 2,3,3-trimethyl-2-butyl, 2,3-dimethyl-2-pentyl,

3-ethyl-3-pentyl, 2,3-dimethy1-2-hexyl, 2,4-dimethyl-2-hexyl, 2,5-dimethyl-2-hexyl, 3-methyl-3 -hexyl, 3-ethyl-3-hexyl, 3,4-dimethyl-3-hexyl, 3,5 -dimethy1-3 -hexyl,

Patented May 4, 1971 2,4-dimethyl-2-pentyl, 3-methyl-3-heptyl, 2,3,3-trimethyl-2-pentyl, 4-methyl-4-heptyl,

2,4,4-trimethyl-2-pentyl, 3-methyl-3-pentyl,

3-ethyl-3-octyl, etc.

l-methylcycloheptyl, 2,7-dimethylcycloheptyl, 4,5-dimethylcycloheptyl, l-methylcyclooctyl, 2,8-dimethylcyclooctyl, 2,5,8-trimethylcyclooctyl, and the like.

Suitable bicyclo[2.2.1]heptyl moieties contemplated by the present invention are, for example, dl-bornyl, dl-isobornyl, dl-fenchyl, l-apocamphyl, dl-endo-Z-norbornyl, and the like. Adamantyl is exemplified by l-adamantyl and Z-adamantyl.

Typical compounds of the present invention include, for example,

2 cyclopentylamino 4 (1-methylcyclopentylamino)- 6- (dl-endo-Z-norb ornylamino -s-triazine,

2 cyclohexylamino 4 (1 adamantylamino) 6 (lmethylcyclohexylamino)-s-triazine,

2 cyclooctylamino 4,6 bis(2-adamantylamino)-striazme,

2 (1 methylcyclopentylamino) 4,6 bis(dl-bornylamino -s-triazine,

2 cyclohexylamino 4 (l-methylcyclohexylamino)-6- (dl-isobornylamino -s-triazine,

2 propylamino 4 (l-adamantylamino)-6-(dl-endo-2- norbornylamino -s-triazine,

2 (3,3 dimethyl 2 pentylamino)-4,6-bis (dl-fenchylamino -s-triazine,

2 (2,3 dimethyl 2 pentylamino)-4-(2,5-dimethylcyclopentylamino) 6 (1 apocamphylamino)-s-triazine,

2 cyclopentylamino 4 cycloheptylamino-6-(2-adamantylamino)-s-triazine,

2 tert butylamino 4 (l-methylcyclopentylamino)- 6-( l-apocamphylamino) -s-triazine,

2 sec butylamino 4,6-bis(1 adamantylamino)-s-triazine,

2 butylamino 4 (Z-adamantylamino)-6-(dl-endo-2- norbornylamino -s-triazine,

2-ethylamino-4,6-bis(dl-bornylamino)-s-triazine,

2 (4,4 dimethyl 2 pentylamino)-4-(l-adamantylamino) -6- (dl-isobornylamino -s-triazine,

2 (3,4 dimethyl-3-hexylamino)-4-(2,7-dimethylcycloheptylamino -6- (dl-fenchylamino -s-triazine,

2 cyclohexylamino 4 cyc1o0ctylarnino-6-(dl-endo-Z- norbornylamino -s-triazine,

2 tert amylamino-4-(3,4-dimethylcyclopentylamino)- 6- (dl-endo-2-norborylamino -s-triazine,

2 (4 octylamino) 4 (l-apocamphylamino)-6-(dlendo-Z-norbornylamino)-s-triazine,

2 tert amylamino 4,6 bis(dl endo 2-norb0rnylamino)-s-triazine, and the like.

The 2,4,6-tris(substituted amino) s triazines of the present invention are colorless, crystalline or glass-like solids at room temperature and are relatively insoluble in water but soluble in many organic solvents such as ethanol, acetone, dimethylformamide, and the like.

The 2,4,6-tris(substituted amino) s triazines of the present invention form non-toxic acid-addition salts with a variety of organic and inorganic salt-forming reagents. Thus, acid-addition salts, formed by admixture of the striazine base with an acid, suitably in a neutral solvent,

are formed with such acids as sulfuric, phosphoric, hydrochloric, hydrobromic, trifluoroacetic, trichloroacetic and related acids. For purposes of this invention, the s-triazine bases are equivalent to their non-toxic acidaddition salts.

The 2,4,6 tris(substituted amino)-s-triazines of the present invention may be readily prepared from cyanuric chloride and alicyclic amines in accordance with the following reaction scheme:

wherein R R and R are as hereinabove defined. When R R and R are all different, the substitution of the amino groups at the 2-, 4- and 6-positions is carried out stepwise as indicated in the above reaction scheme employing equimolar amounts of amine and cyanuric chloride or 2,4-dichloro-6-(substituted amino)-s-triazine, respectively, in the first two steps and an excess of amine and 2-chloro-4,6-bis(substituted amino)-s-triazine in the final step. The substitution of the amino groups need not be carried out in the order shown in the above reaction scheme but may be carried out in any order. When two of the groups are to be the same, then two molecular equivalents of an amine are reacted with cyanuric chloride followed by treatment of the intermediate 2-chloro-4,6- bis(substituted amino)-s-triazine with an excess of the other amine. Alternatively, when two of the groups are to be the same, one molecular equivalent of an amine is reacted with cyanuric chloride followed by treatment of the intermediate 2,4-dichloro-6-(substituted amino)-s-triazine with an excess of the other amine. When R R and R are the same, then cyanuric chloride is treated with an excess of the appropriate amine to produce the corresponding 2,4,6-tris( substituted amino)-s-triazine.

The above reactions may be carried out in an inert solvent such as toluene or xylene for a period of time of from about 3 hours to 24 hours or more at temperatures ranging from about 25 C. to about 200 C. Alpha-pyridone may be used as catalyst in the above reactions or as the reaction solvent. Variation in the reaction time an temperature is dependent upon the structure of the amine reagent; less sterically hindered amines reacting most readily whereas sterically hindered amines react with more difiiculty. When one or two molecular equivalents of amine are used, then an acid scavenger such as sodium bicarbonate, soda ash, or a tertiary amine such as diisopropylethylamine should be employed to take up the hydrochloric acid produced in the reaction. In those cases where an excess of alicyclic amine may be used, then an acid acavenger and/ or an inert solvent may be dispensed with.

The preparation of symmetrical 2,4,6-tris(adamantyl or bicyclo[2.2.1]heptylamino)-striazines may be carried out by reacting cyanuric chloride with an excess of the amine in dilute aqueous sodium hydroxide or potassium hydroxide at the reflux temperature for a period of time of from about 3 hours to about 48 hours, or by use of an organic solvent as described above. The preparation of these compounds can be accomplished by the trimerization of the cyanamides, RNHCN. The products may be separated from the reaction mixtures and purified by standard techniques well known to those skilled in the art.

The 2,4,6-tris(substituted amino)-s-triazines of the present invention are active against Mycobacterium tuberculosis H37Rv infections in mice when tested in accordance with the following procedure. Carworth Farms CFl white mice, females, 4 to 6 weeks old, weighing 17 to 22 grams, are infected with Mycobacterium tuberculosis H37Rv by administration intravenously of 0.2 ml. of a buffered saline suspension containing approximately 1.5 mg. per ml. wet weight of a 12 to 14 day culture of the test organism grown on Sautons agar medium. Routinely, 200-300 mice are given this standard infection and then segregated in a random manner into cages each of which holds five or ten mice. Four groups of five mice each are retained as untreated controls, and the remaining mice are used to ascertain activity of compounds under test. During a one year experience with this test, the standard infection defined above caused a 99.5% mortality, in that 756 of the 760 infected untreated control mice died within 28 days, the normal period of the test.

A measured amount of each compound to be tested is administered orally incorporated in a Standard Diet to groups of infected mice for 14 days, after which the mice are fed untreated Standard Diet. Control animals receive untreated Standard Diet for the entire test period and all animals are allowed to feed at will. Tests are terminated 28 days after the day of infection. A compound is judged active if it either saves 2 or more of. the 5 mice in a test group in two tests or prolongs average survival time by 4 or more days compared to untreated controls.

The Standard Diet used in this test procedure is a commercial feed designed for laboratory mice and rats composed of the following ingredients: Animal liver meal, fish meal, dried whey, corn and wheat flakes, ground yellow corn, ground oat groats, dehulled soybean meal, wheat germ meal, wheat middlings, cane molasses, dehydrated alfalfa meal, soybean oil, brewers yeast, dried yeast, irradiated dried yeast (source of vitamin D riboflavin, niacin, calcium pantothenate, chlorine chloride, vitamin A palmitate, D-activated animal sterol, a-tocopherol, dicalcium phosphate, thiamine hydrochloride, menadione sodium bisulfite (source of vitamin K activity), salt and traces of: maganous oxide, copper sulfate, iron carbonate, potassium iodate, cobalt sulfate, and zinc oxide. The said commercial feed has the guaranteed analysis as containing a minimum of 24.0% crude protein, a minimum of 4.0% crude fat and a maximum of 4.5% crude fiber and is sold under the trademark Wayne Lab-Blox by Allied Mills, Inc., Chicago, Ill. In the test procedure described hereinabove, the Standard Diet into which measured amounts of the test compounds had been homogeneously incorporated was administered to infected test animals, whereas untreated Standard Diet was given to infected control animals.

In a representative operation, and merely by way of illustration, the following compounds of the present invention are active in this test procedure at the indicated oral dose as set forth in Table I below:

No'rE.Infected, non-treated controls: 100/100 mice died with an average survival time of 19 days.

The following examples illustrate the preparation of typical 2,4,6-tris(substituted amino)-s-triazines of the present invention.

5 EXAMPLE 1 Preparation of 2,4,6-tris(1-adamantylamino)- s-triazine A filtered solution of 5.53 g. (0.03 mole) of Cyanuric chloride in 50 ml. of xylene was added dropwise to a slurry of 22.4 g. (0.12 mole) of l-aminoadamantane hydrochloride and 31 g. (41 ml., 0.24 mole) of diisopropylethylamine in 150 ml. of xylene contained in an icecooled flask. The mixture is refluxed for 98 hours and then is transferred to a Parr bomb and heated at 200 C. for 24 hours. The reaction mixture is mixed with water and adjusted to pH 8.0. The xylene layer is further washed with water, dried and evaporated to a waxy solid. This material is triturated with methanol and water to yield 11.8 g. of crude product. Several recrystallizations from ethanol yields 4.3 g., M.P. 242244 C. Further recrystallization from ethanol yields 3.0 g. of purified material, M.P. 243-244 C.

EXAMPLE 2 Preparation of 2,4,6-tris(dl-endo-2-norbornylamino)- s-triazine A filtered solution of 5.53 g. (0.03 mole) of cyanuric chloride in 50 ml. of xylene was added dropwise to an ice-cold stirred slurry of 17.6 g. (0.12 mole) of dl-endonorbornyl-Z-amine and 31 g. (41 ml., 0.24 mole) of diisopropylethylamine in 150 ml. of xylene. After addition is completed the mixture is refluxed for 20 hours. The cooled reaction mixture is treated with water to dissolve the oily lower phase which separates. The xylene layer is extracted with another portion of water, and dried and evaporated to a crude solid. Two recrystallizations from ethyl acetate yielded 3.0 g.. M.P. 214220 C., and a second crop of 3.5 g., M.P. 208-214 C.

EXAMPLE 3 Preparation of 2,4-bis(l-methylcyclohexylamino)- 6-chloro-s-triazine A solution of 5.53 g. (0.03 mole) of cyanuric chloride in 50 ml. of xylene was added at -5 C. to 7 g. (0.062 mole) of l-methylcyclohexylamine and 10.6 ml. (0.062 mole) of diisopropylethylamine in 100 ml. of xylene. After 16 hours of refluxing the xylene was washed with water, dried and evaporated to yield 6.0 g. of product.

EXAMPLE 4 Preparation of 2-(l-adarnantylamino)-4,6-bis(1- methylcyclohexylamino -s-triazine A mixture of 0.12 mole of the 2,4-bis(l-methylcyclohexylamino)-6-chloro-s-triazine mentioned in Example 3, 22.4 g. (0.12 mole) of l-aminoadamantane hydrochloride and 31 g. (0.24 mole) of diisopropylethylamine in 150 ml. of xylene was heated in a Parr bomb for 24 hours at 200 C., and then worked up as described in Example 3.

EXAMPLE 5 Preparation of 2- (dl-endo-2-norbornylamino) 4,6-bis l-methylcyclohexylamino -s-triazine This compound was made similarly to the one described in Example 4, except that 2-norbornylamine Was used in place of l-aminoadamantane, and the last step was run at 170 C. for 24 hours in a Parr bomb.

EXAMPLE 6 Preparation of 2-cyclopropylamino-4-( l-methylcyclohexylamino) -6-( l-adamantylamino -s-triazine This compound was made by the stepwise procedure indicated in Example 9 reacting l-methylcyclohexylamine first, then aminoadamantane, and last cyclopropylamine. The first two steps were done in refluxing xylene, the last in a Parr bomb with 3 molar equivalents of cyclopropylamine at 150 C. for 24 hours.

6 EXAMPLE 7 Preparation of 2,4-bis( l-adamantylamino)-6-(2,4,4-

trimethyl-Z-pentylamino) -s-triazine A solution of 5.53 g. (0.03 mole) of cyanuric chloride in 50 ml. of xylene was added to a solution of 11.2 g. (0.06 mole) of l-arninoadamantane hydrochloride and 15.5 g. (0.12 mole) of diisopropylethylamine in ml. of xylene. The solution was refluxed for 16 hours. The xylene was evaporated at reduced pressure and the residue was transferred to a Parr bomb containing 11.7 g. (0.09 mole) of t-octylamine. This mixture was heated at C. for 24 hours and then extracted with ethyl acetate. The ethyl acetate was washed with water, dried and evaporated to give the desired product.

EXAMPLE 8 Preparation of 2- l-adamantylamino) -4,6-bis (2,4,4- trirnethyl-Z-pentylamino) -s-triazine This compound was prepared similarly to the one described in Example 7, except that 0.03 mole of l-aminoadamantane hydrochloride was used in the first step, and 0.18 mole of t-octylamine was used in the second step.

EXAMPLE 9 Preparation of 2-(l-adamantylamino)-4-cyclohexylamino-6- 2,4,4-trimethyl-2-pentylamino -s-triazine A solution of 5.53 g. (0.03 mole) of cyanuric chloride in 50 ml. of xylene was added at 05 C. to a slurry of 5.6 g. (0.03 mole) of l-aminoadamantane hydrochloride and 5.2 g. (0.06 mole) of diisopropylethylamine in 150 ml. xylene The stirred mixture was refluxed for 16 hours, whereupon 3.87 g. (0.03 mole) of tert-octylamine and 2.6 g. (0.03 mole) of diisopropylamine was added. The mixture was refluxed for 16 hours, whereupon 5.94 g. (0.06 mole) of cyclohexylamine was added. After an additional 16 hours of refluxing, the xylene was washed with water, dried and evaporated to yield the unsymmetrical product.

EXAMPLE 10 Preparation of 2,4,6-tris(2-adamantylamino)-s-triazine This compound is prepared similarly to the l-adamantyl compound of Example 1, substituting an equal amount of Z-aminoadamantane hydrochloride for the l-aminoadamantane hydrochloride of that example. Also, the 98 hour reflux period is omitted and the reaction is completed in a Parr bomb at 200 C. for 48 hours.

EXAMPLE 11 Preparation of 2,4,6-tris(apocamphyl-l-amino)-s-triazine Using equimolar amounts of apocamphyl-l-amine (1- amino 7,7 dimethylbicyclo[2.2.1]heptane) and diisopropylethylamine, this compound is prepared similarly to the tris(l-adamantylamino) -s-triazine of Example 1.

EXAMPLE 12 Preparation of 2,4,6-tris(dl-fenchylamino)-s-triazine Cyanuric chloride (0.03 mole) and 0.27 mole of dlfenchylamine (2 amino 1,3,3 trimethylbicyclo[2.2.1] heptane) are heated in 150 ml. of xylene at 200 C. for 48 hours to give the desired product.

EXAMPLE 13 Preparation of 2,4,6-tris(d-isobornylamino)-s-triazine One equivalent of cyanuric chloride is reacted with four equivalents of d-isobornylamine (d-exo-2-aminocamphane) in the presence of four equivalents of diisopropylethylamine in xylene at 200 C. for 48 hours.

Similarly, other isomeric 2-aminocamphanes give the corresponding tris(Z-aminocamphanyl)-s-triazines. These isomers are l exo 2 aminocamphane (1 isobornylamine) and dand l-endo-2-aminocamphanes (dand 1- bornylamines) 7 EXAMPLE 14 Preparation of 2 (1 adamantylamino) 4 (2,5 dimethyl 1 pyrrolidino) 6 (2,4,4 trimethyl 2- pentyl amino -s-triazine This product was prepared similarly to 2-( l-adamantylamino) 4 cyclohexylamino 6 (2,4,4 trimethyl-Z- pentylamino)-s-triazine, Example 9, with the exception that 2,5-dirnethyl-l-pyrrolidine (5.94 g., 0.06 mole) was used instead of cyclohexylamine.

We claim:

1. A compound selected from the group consisting of those of the formula:

2. A compound according to claim 1 wherein R R and R are l-adamantyl.

3. A compound according to claim 1 wherein R R and R are dl-endo-2-norbornyl.

4. A compound according to claim 1 wherein R is 1- adamantyl and R and R are l-methylcyclohexyl.

5. A compound according to claim 1 wherein R is d1- endo-Z-norbornyl and R and R are l-methylcyclohexyl.

6. A compound according to claim 1 wherein R is 1- adamantyl, R is l-methylcyclohexyl and R is 2,4,4-trimethyI-Z-pentyl.

7. A compound according to claim 1 wherein R is dlendo-Z-norbornyl, R is l-methylcyclopentyl and R is 2,4,4-trimethyl-2-pentyl.

8. A compound according to claim 1 wherein R R and R are Z-adamantyl.

9. A compound according to claim 1 wherein R R and R are 1-apocamphyl.

10. A compound according to claim 1 wherein R R and R are d-isobornyl.

References Cited UNITED STATES PATENTS JOHN M. FORD, Primary Examiner US. Cl. X.R. 

